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Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.
Yu Chen, H, Dina, C, Small, AM, Shaffer, CM, Levinson, RT, Helgadóttir, A, Capoulade, R, Munter, HM, Martinsson, A, Cairns, BJ, et al
European heart journal. 2023;44(21):1927-1939
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Plain language summary
Aortic stenosis (AS) is a form of heart disease that is an abnormal narrowing of the aortic valve in the heart, which restricts blood flow. Although being over the age of 75 appears to increase the risk for development, it is unclear as to who else may be at risk. A better understanding of genetic factors, which may be involved in its development could better help to identify those at risk. This meta-analysis of 10 cohort studies aimed to determine genetic contributors to AS and possible mechanisms involved. The results showed that 15 different gene variations were strongly associated with AS including those in the CELSR2-SORT1, NLRP6, LPA and SMC2 genes. Interestingly some of these genes were also identified in individuals with African and Latin American ancestry. It was concluded that these genes, many of which are associated with hardening of the arteries, altered lipid metabolism, excess storage of fat, and inflammation may all contribute to AS. This study could be used by healthcare professionals to understand that there are specific genetic contributors to the development of AS and that in the future we may be able to target these to identify high-risk individuals and use them in therapeutic management.
Abstract
AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.
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Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.
Wing, RR, Bolin, P, Brancati, FL, Bray, GA, Clark, JM, Coday, M, Crow, RS, Curtis, JM, Egan, CM, Espeland, MA, et al
The New England journal of medicine. 2013;369(2):145-54
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Weight loss is recommended for overweight or obese patients with type 2 diabetes as it increases glycaemic control, reduces risk factors of cardiovascular disease and improves overall quality of life. These benefits, however, are based on short-term studies and the long-term effects of weight loss in this population have not been examined. The aim of this randomised trial was to elucidate whether an intensive lifestyle intervention of weight loss and increased physical activity would decrease cardiovascular morbidity and mortality in overweight or obese adults with type 2 diabetes. Participants were either assigned to an intervention group receiving diet and exercise counselling, or a control group receiving diabetes support and education. A total of 5145 patients were enrolled in the study and the median follow-up was nearly 10 years. The findings of this study showed that an intensive lifestyle intervention did not reduce the risk of cardiovascular morbidity and mortality, as compared with a control programme of diabetes support and education, among overweight and obese patients. While this primary outcome was not reduced, participants in the intervention group experienced various clinically beneficial outcomes throughout the follow-up period.
Abstract
BACKGROUND Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients. METHODS In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. RESULTS The trial was stopped early on the basis of a futility analysis when the median follow-up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P=0.51). CONCLUSIONS An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others; Look AHEAD ClinicalTrials.gov number, NCT00017953.).